I was the president of Pfizer Global Research and Development in 2007 where I managed more than 13,000 scientists and professionals in the United States, Europe, and Asia. I've received numerous awards including an Honorary Doctor of Science degree from the University of New Hampshire. I am also the author of "Drug Truths: Dispelling The Myths Of R&D" and the recently published Devalued And Detrusted: Can The Pharmaceutical Industry Restore Its Broken Image?" I am also a senior partner at PureTech Ventures.

Bad Pharma? Maybe. But Goldacre's Selective Use of Data Is Wrong

Ben Goldacre is now on a North American tour promoting his book, Bad Pharma, his expose of the pharmaceutical industry. On the book’s overleaf, he has the following quote:

“The tricks and distortions documented in these pages are beautiful, intricate, and fascinating in their details.”

Actually, the same can be said for examples that Goldacre uses to make various points in his book. Goldacre has major concerns about the need for more transparency when it comes to making data from clinical trials publicly available. In fact, he spends about one-third of Bad Pharma discussing this topic. I agree that one of the big challenges that the industry faces is the need to be more transparent about its work and I have written about this both on this blog and in Devalued & Distrusted. However, Goldacre’s cherry-picking of data to fit his arguments is inappropriate and infuriating to those who know something about the pharmaceutical industry.

Right at the outset of Bad Pharma, Goldacre tells the story of TGN1412. This is a horrific tale of six young males who, in 2006, volunteered for a phase 1 study for a novel drug, TGN1412. Phase 1 is the very first step in the study of a new drug in people. It is simply meant to test the drug, initially at very low doses, to see how well tolerated it is. TNG1412 was an antibody designed to stimulate the immune system and, in doing so, fight cancer in a whole new way. The hope for TGN1412 was to have it used to treat a rare form of leukemia.

Unfortunately, the volunteers in this phase 1 trial suffered immediate and severe side-effects. These men experienced an immunological firestorm in that the antibody caused the uncontrolled release of toxins. As a result, the volunteers suffered severe adverse events starting with rapid blood pressure lowering, then respiratory issues, kidney failure, etc. Fortunately, thanks to extraordinary efforts by excellent doctors in London Hospitals, all survived.

Goldacre’s purpose in telling this story is that he feels this episode could have been prevented in two ways. First, since this is an unprecedented experimental treatment, the drug should have not been given to six volunteers simultaneously, but rather in a staggered process. He is correct on this. Had this been done, only one volunteer would have been endangered. But his second concern is a real stretch. He believes that a study done ten years earlier by an academic researcher on a single subject could have foretold the events with TGN1412. Unfortunately, this result was never published. Goldacre uses this example to support his argument that pharma selectively publishes data and, in doing so, harms patients.

Here is what Goldacre does NOT tell you about TGN1412.

1) TGN1412 was being developed, not by a pharma company, but by TeGenero, a biotech company with 15 employees that was formed based on work done at the University of Wurzburg. TeGenero, a 15 person company, was not exactly a big pharma.

2) This was known to be a controversial area of research as people were worried that toying with the immune system could have dire consequences. Thus, experts in the field urged caution. The risks were well understood without the need of knowing about a single experiment 10 years earlier. My guess is that some experts would not agree that this isolated incident was truly relevant to the TNG1412 case.

“It is certainly possible to change the way in which novel agents are tested to minimize the number of subjects who are put at risk. As long as we continue to manipulate biology in new ways, we probably cannot prevent all such events from occurring. We must do what we can to minimize risk, but the future health of the world population demands that we not let adverse events put an end to medical progress. We must treat those at risk with respect and great care, but the work must go on.” Dr. Jeffrey M. Drazen

Given this additional background, it is hard to see why Goldacre uses this example to support his arguments. Perhaps it to use sentences like: “Their fingers and toes went flushed, then brown, then black, and then began to rot and die.” That should certainly raise the ire of the general public. Unfortunately, this case is being used for sensationalism and not to advance the cause that Bad Pharma claims to espouse.

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I could not agree more. ‘Bad Pharma’ is replete with bias and error as I have pointed out in my blogs too (http://numedicus.co.uk/blog). It is somewhat ironic that Goldacre complains about inaccurate claims in pharmaceutical marketing, but plays fast and loose with the facts in the marketing of his multi-million dollar earning book. It is also a pity that his laudable aim of better data is focussed so partially on some sectors of the healthcare chain. While recognising that off-label prescribing faces daunting data limitations and can happen ‘on a [physician's] whim’, Bad Pharma does not take the obvious next step, connecting the paroxetine scandal with such behaviour and asking how can we minimise it in future? Could it be related to the author’s own profession?

I don’t discuss the TGN1412 case to “trash” phase one trials, I give it as an example of how people can be harmed when the results of research are not disseminated.

It is very peculiar for John LaMattina to give this as an example of selective use of data. This isn’t about selective use of data. LaMattina simply disagrees with an argument: that the results of phase one trials should be disseminated, to avoid harm to other phase one trial participants in future.

It is also very odd for LaMattina to suggest that this is some wild idea that I have invented myself. As explained in the book – as LaMattina knows – this idea isn’t mine, it comes from the official government report into what went wrong in the TGN 1412 phase one trial.

Here is what that official government review says, on pages 86-87, for those who wish to read it themselves:

“Sharing of information “Pre-clinical studies “It would seem essential to attempt the collection of unpublished pre-clinical information relevant to the safety of human subjects in first-in-man trials to inform the planning of future trials with similar agents. A UK or European database could be linked with others in different countries to form a global database. There is some indication that the pharmaceutical and biotechnology industries and research funding bodies would be willing to explore the sharing of information in this way, and researchers from other sectors, such as academic centres and research institutions might also contribute. – Developers of medicines, research funding bodies and regulatory authorities should expedite the collection of information from unpublished pre-clinical studies relevant to the safety of human exposure. As a first step this should focus on pre-clinical reports of results that signal potential danger to humans with the use of a higher risk medicine or group of medicines. This could provide a platform for information sharing between regulators at EU and international level, e.g. in the form of a confidential database. The submission of such data to a database by the investigators is strongly encouraged. “We believe that the ultimate goal should be an open access database, and the feasibility of this needs to be explored. To avoid the risk of delay in sharing safety-critical information, reports from studies that would otherwise not be in the public domain could initially be stored in a secure database accessible only to regulators worldwide, with frequent review of the reason for delaying open access. ”

So the “ selective use of data” is in fact an argument that LaMattina doesn’t like, and the argument which he claims is some wild idea of mine is in fact one of the findings of the official report into this phase one trial.

I believe that industry and LaMattina are wrong to fear transparency around clinical trial results, and wrong to campaign – so misleadingly – against those who raise the issue in public. Doctors and patients need to know the results of all clinical trials, to make informed decisions about treatments. It is also important for researchers to know what has been tried before, to avoid disasters like TGN1412, as the official UK government report states (years before I explained their conclusions in my book).

GSK have already signed up to our campaign at alltrials.net, as have over 80 patient groups, and research funders such as the Wellcome Trust, and the UK Medical Research Council. As GSK recognise, it is in industry’s interests to embrace transparency, and they are harming themselves with this desperate campaign to justify withholding unflattering trial data. As I explain in the book, there is no medicine without medicines, we need industry to develop good drugs, but there is no free pass to mislead doctors and patients: it is entirely fair and reasonable to expect that we should be able to know the true effects of these treatments, by seeing all trial results.

It is remarkable that an industry which makes lifesaving products should manage to destroy public goodwill, with this ill-advised campaign against those who simply argue for transparency around clinical trials. You can make money off truly good drugs, without hiding data.

Dr. Goldacre, It’s amazing how you obfuscate the premise of my post by going off on tangents. This is not about Phase 1 trial information dissemination. This is about your selective use of data to sensationalize an unfortunate incident that had nothing to do with publishing Phase 1 trial results. Scientists were well aware of the potential issues of phase 1 trial with TGN1412. This is probably why the small biotech company developing this compound started in the clinic at a dose 1/500th of the no effect level in animals. I did agree with your point in the book that the six patients should NOT have been dosed all at the same time. As I said in the post, had the CRO dosed only one volunteer on day 1, the other 5 would not have been harmed. That’s what a responsible company would have been done in this situation. However, as we are on this topic, I find it offensive that you are subtly trying to take credit for GSK’s decision to allow public access to their clinical trial data. They made this decision public LAST OCTOBER before publication of “Bad Pharma”. My guess is that this decision was in the making months earlier at GSK. You should have applauded them way back then, not after your book came out.

Nobody is changing the subject. You are angry about my suggestion that sharing phase one trial results might have helped prevent the awful outcome in the TGN1412 trial. But this isn’t my suggestion. As I explain above, and in the book: this isn’t my idea, it’s one of the conclusions of the official UK government inquiry into the TGN1412 trial. I’ll post the link again, it’s pages 86-87

I don’t know why you’re attacking me for sensationalism in suggesting that sharing phase one results might help prevent outcomes like the TGN1412 episode, when that is a conclusion of the official UK government inquiry into the TGN1412 episode. I think you have made a mistake.

You are also wrong about GSK. In 2012 GSK committed to set up a panel to permit specific researchers to apply for access to anonymised individual patient data files for clinical trials going back to 2007.

http://www.nature.com/news/drug-firm-to-share-raw-trial-data-1.11604

In signing up to support the alltrials.net campaign they have committed to releasing all Clinical Study Reports, going back to the creation of GSK in 2000, to the public, for all currently available treatments.

It’s great that GSK have done this. All of us at the alltrials.net campaign are delighted, and GSK take full credit for making this excellent commitment to transparency. They join over 80 patient groups, the Wellcome Trust, the UK Medical Research Council, and more. I hope many other drug companies will follow GSK’s excellent lead on this issue.

I do find it somewhat mealy mouthed of you to try and say that all you are doing is presenting the conclusions made from a government enquiry. I think John’s point is that the way you do this is sensationalist and could be presented in a far more balanced way, and I think he has put forward some useful facts that would have served to this end. I think the same general criticism could be levelled against the book overall, which often sees conspiracy in every corner and therefore reads like a several hundred page Daily Mail article. For what it’s worth, I think the most egregious lack of balance lies in the title itself – surely “Bad Academia, Bad Journals, Bad Regulators, Bad Doctors and Bad Pharma” would actually be more apt, but I guess that might make the book a little less appealing to the baying middle-classes.

This is all somewhat unfortunate as it significantly dilutes the important points you raise, is hypocritical given the critiques you make around the pharma industry cherry-picking data, and makes your voice sound rather shrill to the people that most need to hear it.

In the spirit of full disclosure, I should say that I am an employee of a large pharmaceutical company. Given this fact, I’m sure your response will dismiss my comments along the lines of “Well you would say that wouldn’t you”.

I would like to point out that through the entire book Goldrace warns about the perils of cherry picking data (and many other practices). Unless we want to assume that readers are completely naïve, one should hope that if they read the book the can learn to look out for this sort of things. So I find the whole criticism risen in this review pretty moot.

So that people can see that LaMattina has deliberately misrepresented the book, and also to show that he knew that sharing phase one trial results is an idea from the UK government report, rather than me, here is that page of the book, in full:

“The Department of Health convened an Expert Scientific Group to try to understand what had happened, and from this two concerns were raised.8 Firstly: can we stop things like this from happening again? It’s plainly foolish, for example, to give a new experimental treatment to all six participants in a ‘first-in- man’ trial at the same time, if that treatment is a completely unknown quantity. New drugs should be given to participants in a staggered process, slowly, over a day. This idea received considerable attention from regulators and the media. “Less noted was a second concern: could we have foreseen this disaster? TGN1412 is a molecule that attaches to a receptor called CD28 on the white blood cells of the immune system. It was a new and experimental treatment, and it interfered with the immune system in ways that are poorly understood, and hard to model in animals (unlike, say, blood pressure, because immune systems are very variable between different species). But as the final report found, there was experience with a similar intervention: it had simply not been published. One researcher presented the inquiry with unpublished data on a study he had conducted in a single human subject a full ten years earlier, using an antibody that attached to the CD3, CD2 and CD28 receptors. The effects of this antibody had parallels with those of TGN1412, and the subject on whom it was tested had become unwell. But nobody could possibly have known that, because these results were never shared with the scientific community. They sat unpublished, unknown, when they could have helped save six men from a terrifying, destructive, avoid- able ordeal. “That original researcher could not foresee the specific harm he contributed to, and it’s hard to blame him as an individual, because he operated in an academic culture where leaving data unpublished was regarded as completely normal. The same culture exists today. The final report on TGN1412 concluded that sharing the results of all first-in-man studies was essential: they should be published, every last one, as a matter of routine. But phase 1 trial results weren’t published then, and they’re still not published now. In 2009, for the first time, a study was published looking specifically at how many of these first-in- man trials get published, and how many remain hidden.9 They took all such trials approved by one ethics committee over a year. After four years, nine out of ten remained published; after eight years, four out of five were still unpublished.”

So where is the criticism of the NIH-sponsors, aka Pure Ethical Serious Scientists, who designed and ran a government-taxpayer funded Prempro study that caused all those CV-events, breast cancers and colon cancers (2002) in asymptomatic women past natural prescribing ages not initiated in actual clinical practice? Those women were hailed as national heroes by the likes of the NIH trial site MD/PhD research sponsors. There was data predicting this CV adverse outcome in cynomolgus monkeys by Clarkson, et. al. at Wake Forest as early as 1994. It doesn’t fit your narrative of scientific ethical lapses emanating from only the for-profit industry?

Oh, and I should mention that when that study was stopped early from the data safety monitoring review board the NIH held a presser with the media 5 full days before practitioners were posted the study information online in JAMA and the NIH still refused to release the full data set to the public for scientific scrutiny and public review until many years later when it was uncovered that adjudicated data adjustments were needed to revise and amend the original publication that was hidden from view. Isn’t that the inverse of politics, over profit, yet created the same scientific moral outcome and conflict?

That not a pharma specific-problem, it looks like a scientific community at-large problem.

I do agree with Ben Goldacre’s basic premise, that there is a lot wrong with big pharma – poor transparency/communication, decision making, bias, etc. – and a lot of this is recognized within big pharma itself. However, I do not agree with the implication that any of this is caused by bad ethics or motives. I can tell you that everybody I know in the industry tries their best to bring greater benefits to the patient, because this is what gives meaning to our work. Even the idea of making more profit is viewed as a means to invest more profit back into innovation, in order to bring better medicines to the patient. But the fact is that big organizations, the human body, and drug development, are all so incredibly complex that we don’t always make the best decisions, despite our best intentions.

Thus, I do think Ben raises some valid issues (even if some specific examples are misinformed), however “Bad Pharma” portrays the industry as fundamentally evil, rather than human and therefore susceptible to mistakes. The fact is we work in this industry because we hope to make a meaningful difference to patients lives, and we could all do better in this regard if we listened to each other, rather than pointing the finger of blame, considering each other as evil, and creating distrust between ourselves when we should be working together toward the same goals.